Intestinal permeability and genetic determinants in patients, first-degree relatives, and controls in a high-incidence area of Crohn's disease in Southern Italy

Am J Gastroenterol. 2005 Dec;100(12):2730-6. doi: 10.1111/j.1572-0241.2005.00325.x.


Objective: A defect of gastrointestinal barrier function is considered to represent an important step in the pathogenesis of Crohn's disease (CD) but the mechanisms leading to an increased intestinal permeability (IP) are poorly understood. Since IP is influenced by pro-inflammatory mediators, it seems likely that a genetically determined abnormal immune response may lead to a loss of barrier function.

Methods: In a geographic area in Southern Italy with high incidence of CD we investigated IP (lactulose/mannitol testing) together with the three main mutations of the NOD2/CARD15 and the D299G polymorphism of the toll-like receptor (TLR)-4 gene in 23 families of CD patients (patients and first-degree relatives).

Results: Forty-eight percent of CD patients and 40% of their healthy relatives were found to have an abnormal IP compared to 5% of an appropriate control population (p < 0.0001). IP, however, was not associated with the L1007finsC mutation of the NOD2/CARD15 or the D299G variant of the TLR-4 gene. Allele frequency of the only L1007finsC mutation of CARD15 was significantly increased in patients (8.7%, p < 0.003) and in relatives (8.3%, p < 0.024) compared with controls (2.4%), whereas the D299G variant of the TLR-4 gene was found to be increased only in relatives (8.3%, p < 0.022), but not in patients (4.3%) compared with the control population (1.7%).

Conclusions: There was no association between IP and genetic markers. Our findings showed a very high proportion of healthy first-degree relatives to bare alterations suggested to constitute determinants of CD. Mutations of NOD2/CARD15 or TLR-4, however, do not lead to permeability defects emphasizing the importance of additional environmental and/or genetic factors for pathogenesis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Capillary Permeability / physiology
  • Case-Control Studies
  • Cohort Studies
  • Crohn Disease / epidemiology*
  • Crohn Disease / genetics*
  • Endemic Diseases*
  • Female
  • Genetic Predisposition to Disease / epidemiology*
  • Genetics, Population
  • Humans
  • Incidence
  • Intestinal Mucosa / pathology
  • Intestinal Mucosa / physiopathology
  • Italy / epidemiology
  • Male
  • Middle Aged
  • Mutation*
  • Pedigree
  • Probability
  • Reference Values
  • Risk Assessment
  • Statistics, Nonparametric
  • Toll-Like Receptor 4 / genetics*


  • TLR4 protein, human
  • Toll-Like Receptor 4